L0301P92 - Antibiotics 2
__TOC__ Antibiotics *substances produced by microorganisms used to inhibit or kill another microorganism Antibacterials *drugs currently used for treatment of bacterial infections are derived from: **natural sources (e.g. aminoglycosides) **semisynthetic (e.g. β-lactams) **synthetic (e.g. sulphonamides) Classification of Antibacterial Drugs *effect - bacteriostatic or bactericidal *chemical structure *target site - mechanism of action Choice of Antibacterial *depends on: **bacterial factors ***infecting organism, resistance status **host factors ***site of infection, allergies, renal/hepatic function, concomitant drugs, age **drug factors ***spectrum of activity, pharmacokinetics, adverse effects profile, cost Drugs That Inhibit Cell Wall Synthesis *most effective on rapidly growing bacteria Target *transpeptidases (PBPs) e.g. β-lactams *transglycosidases e.g. glycopeptides *polypeptides e.g. bacitracin 'β-lactams' *include **penicillins e.g. amoxycillin **cephlasporins e.g. cephalexin **carbapenems and monobactams *irreversible inhibition **inhibit synthesis of peptidoglycan cell wall by inhibition of polymer cross-linking **in growing cells —> lysis and cell death ***i.e. are bactericidal *spectrum of activity determined by: **ability to bind different types of PBPs **ability to penetrate cell to reach target ***Gram+ve easier access than Gram-ve 'Activity' Pros *act synergistically with other antibacterials **e.g. increased penetration of cell wall by aminoglycosides Cons *hypersensitivity reactions **react and make amino groups on proteins antigenic —> immune response **dose-dependent **cross-react (e.g. ampicillin with penicillin) 'Resistance - β-Lactamase' *innate resistance in some bacteria which produce enzyme β-lactamase *cleave β-lactam ring —> inactivate drug *to overcome: **co-administer β-lactamase inhibitor **e.g. clavulanic acid ***an ineffective β-lactam itself that is preferentially broken down 'Penicillins ' *example: amoxycillin, ampicillin, methicillin, flucloxacillin, piperacillin, procaine penicillin *4 groups based on spectrum of activity and sensitivity to β-lactamases *used for: **infections caused by sensitive organisms ***including community-acquired pneumonia, sinusitis Example: Amoxycillin *moderate spectrum **broad spectrum with clavulanic acid *preferred drug *considered safe to use for pregnant and breast feeding women *adverse effects: **nausea, diarrhoea **hypersensitivity rash **anaphylaxis rare but can be fatal **superinfection (if prolonged treatment) *precautions: **renal excretion ***i.e. dose reduction if renal impairment **allergies and cross-reactivity 'Cephalosporins' *examples: cephalexin, cefaclor, cefotaxime *classified by spectrum of activity, sensitivity to β-lactamases and cephalosporinases *used for: **rarely drugs of first choice **can be used in penicillin-sensitive patients Example: Cephalexin *moderate spectrum *safe to use in pregnancy and breastfeeding *orally active **mostly given parenterally (via IM or IV) *adverse effects: **common: diarrhoea, nausea, vomiting **can cause hypersensitivity reactions **opportunistic infections - e.g. thrush **rare: neurotoxicity (confusion, seizures) *precautions: **renal excretion = dose reduction 'Glycopeptides' *inhibit transglycosidases - bactericidal *not first line treatment *used only for severe infections resistant to other drugs e.g. endocarditis *resistance common **e.g. Vancomycin resistant enterococci ***potential nosocomial infection 'Vancomycin' Guidelines for use *made due to emergence of VRE *serious infections caused by organisms resistant to penicillins (e.g. MRSA; MRSE) *Clostridium difficile associated disease *antibacterial prophylaxis for endocarditis **following procedures in penicillin hypersensitive people *surgical prophylaxis **major procedures involving prostheses implantation in institutions with a high rate of MRSA or MRSE Pharmacokinetics *large molecule & lipophilic *not absorbed orally (use for GI infections) *renal excretion Adverse Effects *common: nausea, vomiting (oral) *“red man syndrome” (if IV too fast) **due to excessive histamine realise *nephrotoxicity and ototoxicity **need to monitor serum levels Drugs That Inhibit Folate Metabolism 'Sulphonamides' *example: sulfamethazole *bacteriostatic **effects decreased in presence of pus *adverse effects include: **allergic reactions (drug fever, rashes) **gastrointestinal disturbances *resistance common *often used in combination with DHF reductase inhibitors 'Dihydrofolate Reductase Inhibitors' *example: trimethoprim *bacteriostatic *mechanism of action: **inhibits DHR in bacteria **less active against mammalian enzyme *used alone and in combination for: **urinary tract infections **prostatitis **some respiratory infections ***pneumocystitis carnii Drugs That Inhibit Protein Synthesis 'Macrolides' *examples: erythromycin, clarithromycin, roxithromycin, azithromycin *bacteriostatic - interferes with movement of ribosome along mRNA *mechanism of action: **reversibly bind 50S ribosomal subunit and blocks translocation movement of ribosome along mRNA *broad spectrum (G+ and some G-) *indications: **used for upper respiratory tract infections in penicillin-sensitive patients **drug of choice for some infections ***e.g. legionella pneumonia; campylobacter enteritis 'Erythromycin' *adverse effects: **serious adverse effects are rare **oral erythromycin poorly tolerated ***therefore GI upset *precautions: **allergic responses can occur **interfere with cardiac function ***may prolong QT interval ***increase chance of arrhythmias **drug interactions ***drugs that inhibit CYP3A4 increase erythromycin **avoid in 1st trimester of pre.g.nancy 'Aminoglycosides' *example: gentamicin, streptomycin, neomycin, tobramycin *bactericidal - causes misreading of mRNA *mechanism of action: **bind irreversibly to 30S ribosomal subunit to inhibit protein synthesis *broad spectrum **enters bacteria via oxygen dependent mechanism **not active against anaerobes 'Gentamicin' *used for: **serious Gram –ve infections **serious systemic enterococcal infections, endocarditis (with β-lactams/vancomycin) **surgical prophylaxis **eye infections *pharmacokinetics: **highly polar therefore limited movement **poor oral absorption; **does not cross blood brain barrier **short half life (2-3 h) but significant PAE ***1/day now recommended *adverse effects: **low therapeutic index **toxicity depends on dose and duration ***nephrotoxicity (common but reversible) ***ototoxicity (maybe permanent) *precautions: **individualise dose with drug concentration monitoring (peak & trough) **therapeutic monitoring 'Tetracyclines' *example: doxycycline, minocycline *bacteriostatic - interfere with binding of tRNA to mRNA-ribosomal complex *mechanism of action: **enter bacteria via active transport and reversibly bind to 30S ribosomal subunit **prevents protein translation *very broad spectrum **G+, some G-, chlamydias, rickettsias *indications: **broad spectrum of activity **used for acne, respiratory tract infections **has activity against some protozoa (e.g. malarial parasite)  'Doxycycline' *adverse effects **GI disturbances ***nausea, vomiting, diarrhoea ***direct irritation and effects on gut flora and thus must be taken with food **chelate valium ***deposit in growing bones = decrease bone growth ***deposit on teeth = discoloured enamel **hepatotoxic, renal damage **photosensitivity - easily sunburnt *precautions: **resistance is a problem **not recommended if hepatic impairment **contraindicated in children <8 years old and in pregnancy after 16-weeks Drugs That Inhibit Nucleic Acid Synthesis 'Fluroquinolones' *example: ciprofloxacin, ofloxacin, norfloxacin, moxifloxacin *bactericidal *mechanism of action: **inhibit topoisomerase (DNA gyrase) ***enzyme involved in DNA supercoiling **inhibit DNA replication, transcription and repair *broad spectrum against G+ and G- *indications: **reserved for proven or suspected infections where alternative agents are ineffective or contraindicated **e.g. complicated UTIs, bone or joint infections, prostatitis 'Ciprofloxacin' *pharmacokinetics: **well absorbed from gut and good tissue distribution **most don’t cross blood brain barrier *adverse effects - infrequent & mild **cartilage damage ***not used for growing children; athletes **tendon damage (especially with corticosteroids or >60 yo) **phototoxicity (rare) *precautions **hepatic metabolism (CYP 450) drug interactions **allergies **increasing worldwide resistance 'Nitroimidazoles' *example: metronidazole; tinidazole *bactericidal *mechanism of action: **chemically reduced in sensitive organisms —> inhibition of DNA synthesis *indications: **Gram- and Gram+ anaerobic bacterial infections **some protozoal infections (e.g. giardia; trichomoniasis) *adverse effects **tinidazole < metronidazole **nausea, headache, dry mouth **metallic taste **interaction with alcohol metabolism —> severe nausea and vomiting 'Rifampicin' *broad spectrum but not used often *mechanism of action: **inhibits RNA polymerase enzyme *indications: **used as part of combination treatment for tuberculosis (anti-mycobacterial) **also for Staphylococcus aureus infections *precautions: **significant drug interactions (hepatic enzyme inducer) **always in combination as resistance develops easily on monotherapy   Tuberculosis *cause: Mycobacterium tuberculosis **complex cell wall and extremely slow growing thus not easy to treat *treatment: combination treatment: **rifampicin **isoniazid **+ pyrazinamide (+ ethambutol) in early stages of treatment Drugs That Inhibit Mycolic Acid Synthesis 'Isoniazid' *mechanism of action: **‘activated’ by M. tuberculosis and inhibits synthesis of mycolic acids **constituents of cell wall *indications: **only used as anti-mycobacterial *precautions: **always in combination as resistance develops easily on monotherapy *adverse effects **allergic skin reactions **fever, hepatotoxicity, haematological changes